Neurofibromatosis type 1 (NF1) is caused by mutations in theNF1gene. The clinical presentation of NF1 includes diverse neurological issues in pediatric and adult patients, ranging from learning disabilities, motor skill issues, and attention deficit disorder, to increased risk of depression and dementia. Preclinical research suggests that abnormal neuronal signaling mediates spatial learning and attention issues in NF1; however, drugs that improve phenotypes in models show inconclusive results in clinical trials, highlighting the need for a better understanding of NF1 pathophysiology and broader therapeutic options. Most NF1 patients show abnormalities in their brain white matter (WM) and myelin, and links with NF1 neuropathophysiology have been suggested; however, no current data can clearly support or refute this idea. We reported that myelin-targetedNf1mutation impacts oligodendrocyte signaling, myelin ultrastructure, WM connectivity, and sensory–motor behaviors in mice; however, any impact on learning and memory remains unknown. Here, we adapted a voluntary running test—the complex wheel (CW; a wheel with unevenly spaced rungs)—to delineate fine motor skill learning curves following induction of anNf1mutation in pre-existing myelinating cells (pNf1mice). We found thatpNf1mutant females experience delayed or impaired learning in the CW, while proper learning inpNf1males is predominantly disrupted; these phenotypes add complexity to the gender-dependent learning differences in the mouse strain used. No broad differences in memory of acquired CW skills were detected in any gender, but gene-dose effects were observed at the studied time points. Finally, nitric oxide signaling regulation differentially impacted learning in wild type (WT)/pNf1, male/female mice. Our results provide evidence for fine motor skill learning issues upon induction of anNf1mutation in mature myelinating cells. Together with previous connectivity, cellular, and molecular analyses, these results diversify the potential treatments for neurological issues in NF1.
1型神经纤维瘤病（NF1）由NF1基因突变引起。该疾病的临床表现涵盖儿童及成人患者多样化的神经系统问题，包括学习障碍、运动技能障碍、注意力缺陷障碍，以及抑郁和痴呆风险增加。临床前研究表明，异常神经元信号传导介导了NF1的空间学习和注意力问题；然而，在动物模型中改善表型的药物在临床试验中显示出不确定的结果，这凸显了深入理解NF1病理生理学和拓展治疗选择的必要性。大多数NF1患者表现出脑白质和髓鞘异常，且已有研究提示其与NF1神经病理生理学存在关联，但目前尚无明确数据支持或反驳这一观点。我们此前报道了髓鞘靶向Nf1突变会影响小鼠少突胶质细胞信号传导、髓鞘超微结构、白质连接性及感觉运动行为，但对学习记忆能力的影响尚不明确。本研究采用自主跑轮测试——复杂跑轮（一种横档间距不规则的跑轮）——来描绘在已存在的髓鞘形成细胞中诱导Nf1突变（pNf1小鼠）后的精细运动技能学习曲线。我们发现pNf1突变雌鼠在复杂跑轮学习中表现出延迟或受损，而pNf1雄鼠的正常学习能力则显著受阻；这些表型使所用小鼠品系中性别依赖的学习差异更加复杂。在任何性别中均未检测到已获得复杂跑轮技能记忆的显著差异，但在研究时间点观察到基因剂量效应。最后，一氧化氮信号调节对野生型/pNf1、雄/雌小鼠的学习能力产生差异化影响。我们的研究结果为成熟髓鞘形成细胞中诱导Nf1突变导致精细运动技能学习障碍提供了证据。结合先前的连接性、细胞和分子分析，这些发现为NF1神经系统问题的潜在治疗策略提供了多元化方向。
肿瘤(癌症)患者之家